This invention relates to the synthesis and resolution of a racemic spiro-hydantoin compound into its optical antipodes. More particularly, it is concerned with the preparation of various optically-active asymmetric sprio-hydantoin compounds, which are known to be of value in the medical control of certain chronic diabetic complications arising from diabetes mellitus. The invention also includes within its scope certain corresponding novel amino and hydantoic acid compounds and the cinchonine salt of optically active hydantoic acid, which are used as intermediates in the aforesaid process.
It is now known that certain optical isomers of various asymmetric spiro-hydantoin compounds are useful as aldose reductase inhibitors and, hence, of value in the treatment of certain chronic diabetic complications such as diabetic cataracts, neuropathy and retinopathy. Included among these agents are such optically-active compounds as (4S)-(+)-6-fluoro-2,3-dihydro-spiro[4H-benzopyran-4,4'-imidazolidine]-2',- 5'-dione (sorbinil), which is described in U.S. Pat. No. 4,130,714 and (5'S)-3'-chloro-5',6',7',8'-tetrahydro-spiro-[imidazolidine-4,5'-quinoline ]-2,5-dione which is disclosed in European Patent Application No. 180,421.
In the past, these optically active compounds have been obtained by various means. For instance, sorbinil was first obtained after resolution of the corresponding dl-compound with 1-brucine and reported as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione in U.S. Pat. No. 4,130,714. Later synthetic developments involved the use of asymmetric induction starting with a ketone precursor (viz., 6-fluoro-2,3-dihydro-4H-1-benzopyran-4-one) and optically-active (S)-.alpha.-methylbenzylamine in the presence of titanium tetrachloride, as reported in the Journal of Organic Chemistry, Vol. 47, p. 4081 (1982) and thereafter obtained by cyclization of S-6-fluoro-4-ureidochromane-4-carboxylic acid, which is in turn obtained by resolution of racemic 6-fluoro-4-ureido-chroman-4-carboxylic acid via diasterometic salts with either D-(+)-(1-phenethyl)amine or L-(-)ephedrine in U.S. Pat. No. 4,435,578; while in U.S. Pat. No. 4,716,113 there is described a multi-step process for preparing sorbinil, starting from 2-(4'-fluorophenoxy)ethyl bromide, wherein the enzyme .alpha.-chymotrypsin is employed to resolve the intermediate known as methyl 4-amino-6-fluorochroman-4-carboxylate into its respective optical antipodes prior to conversion to the desired spiro-hydantoin ring compound via treatment with an alkali metal cyanate in an acid medium.
More recently, a three step process for resolving a racemic sprio-hydantoin compound was reported in U.S. Pat. No. 4,952,694. This process involves reacting said racemic compound with an optically-active asymmetric isocyanate to form the corresponding diastereomeric uredio compound. Separated ureido diastereomers are converted to the corresponding asymmetric hydantoin compounds by treatment with an alkali metal lower alkoxide followed by acidification, whereupon the desired optical isomer is obtained.